Skip to Main Content

A Political History of Patient Safety and Human Subject Ethics in Randomized Controlled Trials

February 11, 2022

February 2, 2022

A Political History of Patient Safety and Human Subject Ethics in Randomized Controlled Trials

Laura Bothwell, PhD, MPhil, MA

ID
7444

Transcript

  • 00:00Welcome to the program for Biomedical Ethics.
  • 00:02Our Evening seminar series,
  • 00:04and we're particularly pleased
  • 00:05tonight because as you know,
  • 00:07we try very hard to bring you
  • 00:09experts in and and and leaders in
  • 00:11ethics from all around the world.
  • 00:13And then we realized that not
  • 00:15infrequently we have some wonderful
  • 00:16people right here at Yale that we'd
  • 00:18like to highlight and bring to you.
  • 00:19And so this evening it's
  • 00:22doctor Laura Bothwell.
  • 00:23Laura is an ethicist and historian
  • 00:25of public health for research,
  • 00:26examines social, historical,
  • 00:28and ethical dimensions of epidemiology.
  • 00:30With a particular focus on
  • 00:32randomized controlled trials,
  • 00:34she has an interest in in vulnerable
  • 00:39subjects and participant diversity
  • 00:42in randomized control trials as well.
  • 00:44She also does work in climate change,
  • 00:46epidemiology and ethics.
  • 00:49Laura's education includes a PhD
  • 00:51from Columbia, a postdoc at Harvard,
  • 00:54and she is.
  • 00:56She is a visiting scholar visiting
  • 00:58appointments at the universe
  • 00:59at Oxford University,
  • 01:01the Fundacion Brocher and the Karolinska
  • 01:03Institute and National Taiwan University.
  • 01:05So she is in fact has visiting
  • 01:08appointments all around the
  • 01:09world and what she teaches public
  • 01:12health ethics right here at Yale.
  • 01:14Very very pleased to welcome Laura
  • 01:16doctor Laura Bothwell this evening
  • 01:18to let you folks know how this works.
  • 01:20We will have about a 45 minute
  • 01:22talk from Doctor Bothwell,
  • 01:24plus or minus a bit,
  • 01:25and then we'll have a conversation.
  • 01:27I'll invite you to submit questions
  • 01:29through the Q&A function INSZOOM.
  • 01:31I'll read these questions to Doctor Bothwell.
  • 01:33I apologize if advanced if I
  • 01:35don't get to your question,
  • 01:36we'll get to as many of them as we can.
  • 01:39Then we will stop no later than 6:30.
  • 01:41So we start now and we ended 6:30.
  • 01:46And with that with no further ado,
  • 01:48I thank you very much for joining
  • 01:50us tonight and I welcome my friend
  • 01:52and my colleague on the faculty
  • 01:53and I'm so pleased to have you
  • 01:55here as our guest speaker.
  • 01:56Tonight, Doctor Laura Bothwell.
  • 01:58Take it away, Laura.
  • 02:00You're muted, there you go.
  • 02:02There we go. Thank you so much.
  • 02:05Doctor Mercurio,
  • 02:06it is such an incredible privilege
  • 02:08to be a part of this seminar series.
  • 02:12I've been really enjoying and learning
  • 02:15a great deal from last year's series,
  • 02:18dealing with anti racism to the very
  • 02:21pertinent and important topics that
  • 02:23have been explored this year as well
  • 02:26with regard to vaccination policy.
  • 02:28So it's just a real privilege to
  • 02:30be a part of this excellent series
  • 02:32and to have had the opportunity
  • 02:34to work with Mark Mercurio and
  • 02:36Sarah Hull who I believe don't just
  • 02:40explore bioethics but live.
  • 02:43In the classic Aristotelian sense of virtue,
  • 02:46ethics,
  • 02:47in their professional dynamics here at Yale,
  • 02:49and it's been just such a such a
  • 02:52privilege and pleasure to be able to
  • 02:55work with this incredible program.
  • 02:58So I'm talking about a political history
  • 03:00of patient safety and human subject
  • 03:02ethics in randomized controlled trials.
  • 03:04This is the subject of a book that
  • 03:07I'm in the process of writing.
  • 03:10To begin,
  • 03:11I'd like to acknowledge support that
  • 03:14I've been fortunate to receive for this
  • 03:18project from the agencies listed here,
  • 03:21and I also would like to acknowledge
  • 03:24the image credits at the bottom
  • 03:26from various archives.
  • 03:27That have allowed public access to
  • 03:31some really useful images that are
  • 03:34being shown in the slides today.
  • 03:37The framework of this talk first
  • 03:39will examine historical influences of
  • 03:42social settings, intellectual trends,
  • 03:44culture, social movements,
  • 03:46economics and regulations on
  • 03:48the development of RCT's.
  • 03:49And we'll examine key themes across time,
  • 03:52methodological rigor, ethics,
  • 03:54political context,
  • 03:55and perspectives toward vulnerable
  • 03:57research subjects.
  • 04:01The format will involve looking at the
  • 04:03origins and early history of clinical trials,
  • 04:06the emergence of randomization,
  • 04:08the expansion of RCTs, then limitations,
  • 04:10and ethical standards in the early use of
  • 04:14RCT's and limitations in unregulated research
  • 04:16with a case study of fill it in mine,
  • 04:18which I'm sure many of you are familiar with.
  • 04:21The emergence of policies in the 1960s
  • 04:23expanding required use of our cities.
  • 04:25The role of the civil rights
  • 04:28movement in advancing trial ethics.
  • 04:30Recent historical.
  • 04:31Improvement and attention to participant
  • 04:33diversity and also recent challenges as
  • 04:36RCT's have globalized and industrialized.
  • 04:39So going into the early history
  • 04:42of randomized controlled trials
  • 04:45prior to the emergence of RCT's,
  • 04:48there was the development of alternate
  • 04:50allocation of patients in trials.
  • 04:52So rather than randomly allocating
  • 04:56participants to intervention
  • 04:58and placebo arms,
  • 04:59early trial is typically would
  • 05:03alternately allocate participants.
  • 05:04But prior to that we had a really.
  • 05:09Disorganized system of of clinical research,
  • 05:12which reflected a completely different
  • 05:14way of thinking about evidence
  • 05:16in public health and medicine.
  • 05:18So clinical trials began to substantially
  • 05:21expand in the mid to late 19th century as
  • 05:25a as a result of shifts in the structure
  • 05:29of medicine and scientific thinking.
  • 05:32In part this was due to the
  • 05:35expansion of hospitals.
  • 05:36Medicine became institutionalized and
  • 05:39shifted from being conducted in patients
  • 05:42homes to collecting sick patients together.
  • 05:46Many of the early hospitals were particularly
  • 05:50targeting impoverished populations,
  • 05:52and we're free hospitals
  • 05:54and charitable hospitals,
  • 05:57and is technology developed overtime
  • 06:00hospitals themselves developed and appeal to.
  • 06:03Patients of all economic backgrounds
  • 06:06for the access to technology, and.
  • 06:09In this process,
  • 06:11medical thinking became more systematized
  • 06:14and institutionalized in a physical sense.
  • 06:19And for the first time we started to
  • 06:21see very large numbers of patients
  • 06:24coming together in the same place.
  • 06:26For frequently the same diseases
  • 06:29in rapid succession,
  • 06:30giving researchers access to considerable
  • 06:33sizes of populations for trials in ways
  • 06:37that they hadn't previously had access to.
  • 06:40So that was one dimension,
  • 06:42but only one dimension of the changing
  • 06:45ways that medical thinking was being
  • 06:47done in the late 19th century.
  • 06:50There was also an increasingly empirical
  • 06:52approach to medicine and public health.
  • 06:54We saw the development of the field
  • 06:57of microbiology really advancing
  • 06:59the germ theory, advancing,
  • 07:01and just like other dimensions
  • 07:04of the sciences, medicine,
  • 07:06and public health began to be much more.
  • 07:10Rigorous and systematized.
  • 07:12And there was an effort in scientific
  • 07:15thinking toward more empirical approaches.
  • 07:18There was also a shift toward
  • 07:21greater professionalism.
  • 07:22In medicine and public health,
  • 07:23which contributed to this more rigorous
  • 07:27approach to thinking about disease
  • 07:31at a more complex and systems level?
  • 07:36And we saw a new biologic vaccine and
  • 07:39drug industries emerge to confront the
  • 07:41newly and recently identified germs.
  • 07:43So now we had not only a better
  • 07:46awareness of the diseases that were most
  • 07:49commonly afflicting global populations,
  • 07:50but we also had new industries and new
  • 07:55interventions that medical practitioners
  • 07:57were eager to test out on patients.
  • 08:00And so all of this led to a conglomeration of
  • 08:04events that made it quite.
  • 08:06Likely for clinical trials to emerge,
  • 08:09and of course, that's.
  • 08:11What we saw happening, however,
  • 08:13in the early days of clinical trials,
  • 08:16there was an absence of regulation
  • 08:18and absence of organization and
  • 08:20a lot of significant problems.
  • 08:22So at this time controlled clinical
  • 08:25trials still conflicted with an
  • 08:27intellectual culture and medicine in which
  • 08:30individualistic ideologies dominated.
  • 08:32This was a sort of transition
  • 08:35toward evidence based thinking,
  • 08:36and of course the field of
  • 08:39evidence based medicine emerged.
  • 08:41A century later, essentially,
  • 08:43but during this time there was a
  • 08:46a real predominance among medical
  • 08:48practitioners that each individual
  • 08:50patient should be treated as such,
  • 08:53and you couldn't necessarily compare
  • 08:55patients from one to the next.
  • 08:58This was sort of the General practitioner
  • 09:01ideology but scientifically minded.
  • 09:06Physicians and researchers were
  • 09:08starting to shift toward a concept
  • 09:12of the common human where we could
  • 09:15at least look at basic responses of
  • 09:18individuals to disease and responses to
  • 09:21interventions against those diseases
  • 09:23and look at trends across groups of
  • 09:26individuals and start to think about.
  • 09:29Controlling for confounders.
  • 09:32However, even when clinical trials occurred,
  • 09:34there were problems.
  • 09:35There were typically small
  • 09:37patient sample sizes.
  • 09:38Control groups were relatively rare.
  • 09:41Methods were loose,
  • 09:43there were poor ethics,
  • 09:45typically no mention of informed
  • 09:47consent or patient rights.
  • 09:49There was really little if any infrastructure
  • 09:51or support for clinical research.
  • 09:54It was wholly unregulated,
  • 09:55and at this time still expert testimonials
  • 09:58and case studies were much more
  • 10:00common in the scientific literature.
  • 10:03In clinical trials and you can see in
  • 10:06this image here that renting Psyche
  • 10:09Psychiatric hospital in New Jersey,
  • 10:11where Henry Cotton became well
  • 10:13known for removing patients teeth,
  • 10:16tonsils,
  • 10:16colons,
  • 10:17and other organs under false
  • 10:19claims of curing mental illness.
  • 10:21And this was one of numerous examples
  • 10:24within the scientific community that
  • 10:27really got those who are thinking
  • 10:29about evidence to move toward having.
  • 10:34Higher standards to hold their
  • 10:37colleagues accountable for
  • 10:38what they believed was the.
  • 10:41The the evidence for their interventions.
  • 10:46Still we saw a predominance in this
  • 10:49era of interventions that were promoted
  • 10:52by either medical practitioners or
  • 10:55by the proprietary companies that
  • 10:59were producing drugs and various
  • 11:03treatments that really had no overall
  • 11:08accountability beyond the claims of.
  • 11:11Those producers and also the physicians
  • 11:14who they periodically paid to promote
  • 11:17their products in medical journals.
  • 11:19And here are some other examples
  • 11:22of descriptions of proprietary
  • 11:24drugs in the early 19th century,
  • 11:26just to give us a real contrast of what
  • 11:29life was like when we didn't have a
  • 11:33robust Food and Drug administration.
  • 11:36So I I like the description here,
  • 11:39of sarsaparilla as something that
  • 11:42is uniformly successful in certain
  • 11:46in its remedial effects it produces.
  • 11:49Rapid and complete cures of a
  • 11:52whole range of indications for all
  • 11:56diseases arising from the impurity
  • 11:58or deficient vitality of the blood,
  • 12:00blood or from mercurial poison is a powerful,
  • 12:04safe and certain remedy,
  • 12:05and this is,
  • 12:06I think,
  • 12:07striking simply for the language
  • 12:10in terms of
  • 12:12how. How much liberty?
  • 12:14The producer of this drug was able
  • 12:18to take in proclaiming perfect,
  • 12:22perfect treatment.
  • 12:24And you know, a power that is.
  • 12:28Available for a variety of conditions
  • 12:31and we don't really have that level of
  • 12:34liberty for producers of products anymore.
  • 12:36As a result of shifts that
  • 12:39we're going to talk about.
  • 12:41So at this time there were other
  • 12:43problems in scientific thinking that
  • 12:46were really affecting the the development
  • 12:49of the field of clinical trials.
  • 12:52There was the eugenics movement
  • 12:55and arguably accomplishing or
  • 12:58accompanying poor research methodology.
  • 13:01There were also dangerous social prejudices
  • 13:04that were influencing scientific thinking,
  • 13:07and so even for those who are starting to.
  • 13:11Think about conducting clinical trials.
  • 13:15There were some real ethical problems
  • 13:18that resulted from the influence of social
  • 13:22context and social prejudices on science.
  • 13:26In a system that was without
  • 13:29regulation and without policies for
  • 13:31protecting vulnerable populations to.
  • 13:33So, to give you a sense of
  • 13:36the early clinical trial,
  • 13:37subjects who we've seen in in.
  • 13:41The number of scenarios of our
  • 13:45more advanced clinical trial
  • 13:47methods in the early 20th century.
  • 13:51The populations that they drew upon
  • 13:55were frequently institutionalized,
  • 13:57impoverished, and marginalized.
  • 13:59For example,
  • 14:00there were cholera inoculations
  • 14:02tested on inmates and it's this
  • 14:05penal settlement in India.
  • 14:07Quinine tested against malaria among inmates.
  • 14:12In the prison labor camp that
  • 14:14undermines penal settlement,
  • 14:15prison label Labor camp in the Bay of Bengal,
  • 14:18Antipyretics were tested among
  • 14:19Burling mothers in a British line
  • 14:22in hospital for low income women.
  • 14:24Tuberculosis treatments were tested among
  • 14:27Native Americans on Western reservations.
  • 14:29The diphtheria antitoxin was tested at
  • 14:32Wheeler Parker Hospital for infectious
  • 14:34diseases among underprivileged
  • 14:36children in New York City and orphans,
  • 14:38also in the hope it all days on fonts Milad.
  • 14:42In Paris,
  • 14:43and so this is a real trend that
  • 14:46we saw occurring in trials in this
  • 14:50in this time period.
  • 14:53OK, now I'm not sure if I should take.
  • 14:56I see there is a hand raise.
  • 14:57I don't know if I should take
  • 14:59questions now or wait until the end.
  • 15:04I I would leave it up to you.
  • 15:05We can. We generally wait till
  • 15:06the end for these things Laura,
  • 15:07but why don't we go ahead and do that?
  • 15:11Great, OK, well we'll be sure that
  • 15:15someone is asking about a recording.
  • 15:16And yes, there is a recording
  • 15:18which we made available later.
  • 15:21And we will. We will absolutely.
  • 15:26We'll absolutely get to the
  • 15:27questions right after Loris talk.
  • 15:29Perfect, yeah, I.
  • 15:30I would love to return to this period
  • 15:34as we move to the end of the talk.
  • 15:36I'd love to come back to this,
  • 15:38so I look forward to those questions.
  • 15:41So there was a sort of really seismic
  • 15:44shift in the way that scientists were
  • 15:47thinking about clinical trials with
  • 15:50the development of the work of Sir
  • 15:53Austin Bradford Hill and the creation.
  • 15:56Of statistical methods,
  • 15:58there's a real overlap in the
  • 16:00history of infectious disease and
  • 16:02the history of the development
  • 16:04of randomized controlled trials.
  • 16:05Austin Bradford Hill himself was
  • 16:09struck ill with tuberculosis and in
  • 16:13his illness he was bedridden and spent
  • 16:16a good deal of time thinking about
  • 16:19medical statistics and developing a
  • 16:22series of articles for The Lancet on
  • 16:24Principles of Medical Statistics.
  • 16:26That could be applied to clinical trials,
  • 16:29and he shifted his professional
  • 16:32focus from work in the in practicing
  • 16:35medicine to becoming an epidemiologist
  • 16:38and thinking about medicine from
  • 16:41a more distanced stance in terms
  • 16:46of the focus of his professional
  • 16:49work from a day to day basis, and.
  • 16:54He developed a series of ideas for
  • 16:57randomization that at the time were
  • 17:01considered completely unethical.
  • 17:03Physicians and researchers felt that
  • 17:06when a new scientific development emerged,
  • 17:09it was not ethical to allocate
  • 17:12patients to a placebo arm,
  • 17:14particularly at random when there
  • 17:17was an opportunity to provide
  • 17:20a cure for for those patients.
  • 17:23And.
  • 17:24A real significant historical moment
  • 17:28occurred following the Second
  • 17:31World War when in London there was
  • 17:35a real economic deficit and there
  • 17:38was not a capacity from it for the
  • 17:43government to provide streptomycin.
  • 17:45This newly developed antibiotic to all
  • 17:48of the patients with tuberculosis who
  • 17:52would stand to potentially benefit from this.
  • 17:55Experimental therapy and so.
  • 17:57Austin Bradford Hill saw this as a a
  • 18:02really opportune moment to conduct
  • 18:05what really has been celebrated as
  • 18:08the first institutionalized very
  • 18:11rigorous multi institution studied.
  • 18:17Applying randomization in a
  • 18:20clinical trial and so.
  • 18:23There's the streptomycin study
  • 18:26for tuberculosis involved.
  • 18:28A placebo group of patients who were
  • 18:31receiving the existing standard
  • 18:33of care for to tuberculosis,
  • 18:34which was bed rest and then an
  • 18:38intervention group who received
  • 18:40streptomycin and it studied these
  • 18:42patients over the course of four
  • 18:45months and looked at the outcomes
  • 18:48for the control and intervention
  • 18:50group and found a significant
  • 18:53benefit from streptomycin and again,
  • 18:56this study was only considered ethical
  • 18:58because the government could not provide.
  • 19:00Enough streptomycin for everyone
  • 19:03who they would have liked to have
  • 19:06provided it for and so as a result,
  • 19:10inevitably there was a percentage
  • 19:12of the patient population that was
  • 19:14not going to receive anything beyond
  • 19:17the existing standard of care.
  • 19:19And so it was deemed ethical to
  • 19:22allocate this placebo group to
  • 19:24the existing standard of care.
  • 19:27At random to conduct this trial,
  • 19:30given the lack of access to resources.
  • 19:33But what was interesting is
  • 19:35that after four months of study,
  • 19:38it became clear that resistance
  • 19:41began to develop to streptomycin,
  • 19:44and so the researchers realized
  • 19:47that it would
  • 19:49be necessary to provide combinations
  • 19:52of antibiotics to really cure
  • 19:55tuberculosis and nice discovery.
  • 19:57Proved to the medical community
  • 20:00that there was some real value
  • 20:02of him having a a rigorous study.
  • 20:05With randomization to the control and
  • 20:08intervention group so that we could
  • 20:11develop more rigorous scientific knowledge
  • 20:14to better treat populations overtime.
  • 20:17And at this point in history,
  • 20:20the concept of clinical aquacise
  • 20:22had not been specifically named,
  • 20:24but this was sort of the genesis
  • 20:27of the concept of clinical aquacise
  • 20:30in scientific thinking that allowed
  • 20:33generations of researchers too then.
  • 20:36I think we feel that it was appropriate
  • 20:40to allocate participants to an
  • 20:42intervention and a control arm at
  • 20:44random when there was no clear
  • 20:47sense that there was necessarily a
  • 20:50benefit of an intervention and that
  • 20:52it was then ethical to continue to
  • 20:56conduct a randomized study until a
  • 20:58preponderance of information had
  • 21:00accumulated sufficient to convince the
  • 21:02clinical community that it was appropriate.
  • 21:06We shipped to a new plan of action,
  • 21:08whether that be the new intervention
  • 21:10or in the case that the intervention
  • 21:13proved iatrogenic reverting to
  • 21:15the existing standard of care.
  • 21:18So there was a process of shift that
  • 21:21occurred in the years following
  • 21:25the original streptomycin study.
  • 21:28First,
  • 21:29you can see historically this is a
  • 21:32chart that I've created from looking
  • 21:35at around 1000 RCT's in the published
  • 21:38literature,
  • 21:39overtime and trends of where trials
  • 21:41have been conducted in various
  • 21:43factors and trials that will be
  • 21:45looking at throughout these slides.
  • 21:47But you can see originally there was a trend.
  • 21:50Trials coming out of the UK.
  • 21:53The group that Austin Bradford
  • 21:55Hill worked with with the Medical
  • 21:58Research Council in the UK did a
  • 22:01series of studies on interventions
  • 22:04for tuberculosis and increasingly
  • 22:06a variety of other interventions.
  • 22:08And then this team started to promote
  • 22:12our success internationally and in
  • 22:15the 1950s and 1960s in the United States,
  • 22:18there was a huge investment in
  • 22:21science in response.
  • 22:22Through the Cold War,
  • 22:23as the US was trying to win the
  • 22:26science race and the NIH received
  • 22:28a an enormous amount of funding
  • 22:31and colleagues at the NIH were very
  • 22:34keen to embrace the methods that
  • 22:37Austin Bradford Hill was promoting
  • 22:39in lectures around the world.
  • 22:42And at this time there was a period for,
  • 22:46you know, the 1960s to the late 1980s, when.
  • 22:52The NIH was a leading funder
  • 22:55of clinical trials worldwide,
  • 22:57and then you would see a shift
  • 23:01toward trials being located in
  • 23:05different nations around the world.
  • 23:07And this was a period when shifts
  • 23:11in trial sponsorship moved toward
  • 23:14industry funding and multinational
  • 23:16trials became much more common.
  • 23:19From this period forward.
  • 23:21But we're following the history of RCT.
  • 23:24Where they have occurred in this
  • 23:26talk and so this also aligns with.
  • 23:29Some significant moments in the
  • 23:32history of bioethics and the patient
  • 23:35protections that we saw develop
  • 23:37for participants in RCT's in this
  • 23:40in this time period,
  • 23:41so I'd like to explore this
  • 23:43a little bit more,
  • 23:44and you can also see on the next slide.
  • 23:48Fairly similar trends in terms of funding,
  • 23:51so the UK Medical Research
  • 23:53Council was an original funder.
  • 23:55Then we have the US Public Health service,
  • 23:57DHS taking a significant role and
  • 24:00then pharmaceutical companies taking
  • 24:02a larger role in more recent history
  • 24:05so RCTs became institutionalized
  • 24:08and expanded in the 1950s.
  • 24:10But they were not required by any regulators,
  • 24:14and they were also not regulated
  • 24:17in terms of ethics.
  • 24:18And any any standards for patient
  • 24:22protections and all of this
  • 24:24would eventually come to a head.
  • 24:26We had post war ethics that had expanded,
  • 24:30but these were not required
  • 24:32or regulated in any sense.
  • 24:34So the Nuremberg code of 1947 has been
  • 24:37historically celebrated celebrated as
  • 24:39a watershed moment for establishing
  • 24:42the requirement of informed consent,
  • 24:45and indeed,
  • 24:46the World Medical Association passed
  • 24:47the resolution on human experimentation.
  • 24:50The principles for those in research
  • 24:52and experimentation in 1954,
  • 24:54which implemented the informed consent
  • 24:57requirement of the Nuremberg Code.
  • 24:59But this was not put into significant
  • 25:02use internationally.
  • 25:03It predated the development of the
  • 25:06intellectual field and discipline
  • 25:09of bioethics,
  • 25:10and also there were no ethical or
  • 25:13regulatory infrastructures to put
  • 25:15the Nuremberg Code into place.
  • 25:17So what happened following the Second
  • 25:19World War is that those scientists?
  • 25:21Who are keen to follow the code?
  • 25:24Did so and those who were not
  • 25:27particularly seeing this as their
  • 25:29primary objective scientifically
  • 25:31continued to do business as usual,
  • 25:34which led to some real significant
  • 25:38problems for patient protections.
  • 25:41So unregulated research came to a
  • 25:44breaking point in the late 1950s
  • 25:47with the solidified crisis,
  • 25:49and here you can see an ad.
  • 25:52From a Swedish.
  • 25:54Producer of solid amide claiming
  • 25:56that it was safe for children.
  • 25:59The drug quality mind was sold
  • 26:03around the world.
  • 26:05And it was widely distributed in
  • 26:08numerous countries and it was sold.
  • 26:12Or it was it was not sold.
  • 26:13It was available in the Dominican Republic,
  • 26:17France, Hungary, in the United States,
  • 26:19which meant that doctors who were
  • 26:23distributing the drug to patients
  • 26:25could do so for experimental purposes.
  • 26:29But it was not yet approved for
  • 26:33Sale by pharmacies. So, uh.
  • 26:37This drug was being widely used
  • 26:41by pregnant women to assist with
  • 26:45warnings sickness.
  • 26:46And a Doctor Who is prescribing this drug.
  • 26:51Doctor Videocine lens in Germany
  • 26:54started to notice a significant
  • 26:57exponential spike in.
  • 27:02Phocomelia, which is a.
  • 27:06A birth defect of children
  • 27:08being born with deformed limbs,
  • 27:11he also saw a rise in stillbirths
  • 27:14and pregnancy is not going to
  • 27:17turn to term and he identified
  • 27:19the link between the rise and the
  • 27:22consumption of The Little Mermaid
  • 27:24and the rise in these birth defects.
  • 27:27And he was ridiculed by Kenny Grunenthal,
  • 27:29the drug company who had created
  • 27:32solidified as a half wait intent
  • 27:34on murdering a drug by spreading.
  • 27:37Rumor but I soon became clear
  • 27:41that he was right,
  • 27:42and the thalidomide epidemic
  • 27:46broke out throughout the world.
  • 27:50It started to be documented
  • 27:53within the medical literature.
  • 27:58And. Alarms really started to be
  • 28:03raised in the US. Frances Kelsey,
  • 28:06who is a pharmacologist and reviewer
  • 28:07for the Food and Drug Administration,
  • 28:10also was concerned about
  • 28:13thalidomide exposure.
  • 28:14And she kept the drug from
  • 28:17being approved by the FDA.
  • 28:20And as news of the crisis
  • 28:22broke out around the world,
  • 28:24she was really celebrated for
  • 28:27having prevented the the drug
  • 28:30from reaching populations.
  • 28:31More broadly, in the United States,
  • 28:33she received the President's
  • 28:36medal for distinguished service.
  • 28:39And in response to all of this,
  • 28:42government leaders realized that we
  • 28:44needed to see some more robust controls
  • 28:48to prevent some sort of epidemic
  • 28:52like this from occurring again.
  • 28:55It was really the determination
  • 28:57and stubbornness of Kelsey who
  • 28:59prevented a broader epidemic in
  • 29:01the United States than occurred
  • 29:03in other parts of the world, but.
  • 29:08Smartly,
  • 29:08the regulators at the time were
  • 29:10seeing that they needed a more robust
  • 29:13infrastructure to prevent this sort
  • 29:15of thing from happening again.
  • 29:17We couldn't simply rely on a plucky
  • 29:21individual in the FDA to to prevent
  • 29:24this sort of incident from occurring,
  • 29:27and so this led to the 1962
  • 29:30Kiefaber Harris amendments.
  • 29:31The Food and Drug Act,
  • 29:33which led to the requirements for
  • 29:35adequate and well controlled studies,
  • 29:37and this was the creation of the
  • 29:39requirement in the expectation that RCT.
  • 29:42Be used for drug approval,
  • 29:44but it also led to the first
  • 29:47legal requirement of informed
  • 29:48consent for research subjects,
  • 29:51so this was a significant moment for
  • 29:54the transition from the Nuremberg Code.
  • 29:58Ideas into an actual regulatory
  • 30:00reality so that studies that were
  • 30:03being brought to the FDA had to
  • 30:06demonstrate that they had obtained
  • 30:09informed consent from research subjects.
  • 30:12And in response to this,
  • 30:13the FDA held a conference on the
  • 30:16amendments and you can see that it was
  • 30:18extremely well attended with standing
  • 30:20room only from members of the drug industry,
  • 30:23and this led to a complete shift
  • 30:25in the way that drugs were approved
  • 30:28and the expectations of having
  • 30:30RCT's before drug approval.
  • 30:34The regulation of research expanded
  • 30:36globally at this point in history,
  • 30:38with a new emphasis on
  • 30:40research ethics as well.
  • 30:41The World Medical Association
  • 30:44Declaration of Helsinki.
  • 30:46Was adopted by the 18th World Medical
  • 30:50Association General Assembly in 1964.
  • 30:52This enshrined the main principles of
  • 30:54the Nuremberg Code demanding informed
  • 30:56consent and respect for research subjects,
  • 30:59and this was incorporated into the
  • 31:01FDA informed consent requirements and
  • 31:04also into other international ethics
  • 31:06regulatory requirements around the world.
  • 31:08So the declaration of Helsinki.
  • 31:12Is ethically binding on physicians,
  • 31:14and that obligation overrides any
  • 31:16national or local laws or regulations.
  • 31:18If the declaration provides
  • 31:20a higher protection,
  • 31:21it requires all research involving
  • 31:23human subjects to be discussed by
  • 31:25a committee with members other
  • 31:27than the researchers,
  • 31:28and this was really a direct reflection
  • 31:30of the problems of the thalidomide crisis.
  • 31:33Because Kenny Groenendaal had been
  • 31:37developing a drug at studied it
  • 31:39internally and it didn't have any sort of.
  • 31:42External review of the research
  • 31:44that the company was doing
  • 31:47on this drug and then the drug was
  • 31:50distributed without any sort of external
  • 31:53accountability and the ethical problems
  • 31:56of this had become very apparent in
  • 31:58the results of the the ELIMITE crisis.
  • 32:01And so this was a time of a shift toward
  • 32:06creating the concept of external review.
  • 32:11So the declaration of Helsinki
  • 32:13also established the principles
  • 32:15of respect for the individual
  • 32:18self-determination and informed consent.
  • 32:20The investigators duty to the
  • 32:21patient or the volunteer.
  • 32:23The subjects welfare must
  • 32:24always take precedence over the
  • 32:26interest of science and society,
  • 32:28and it also had allowances for vulnerable
  • 32:32research participants and so in
  • 32:35response to this regulatory shift and
  • 32:38the requirement of informed consent.
  • 32:41And the incorporation of the
  • 32:44Declaration of Helsinki into clinical
  • 32:47research standards by regulators.
  • 32:49We also saw a significant rise in a
  • 32:52stated use of informed consent in
  • 32:55published RCT's that only increased
  • 32:58overtime until more recent years,
  • 33:01when perhaps it became simply assumed.
  • 33:05We also saw following this period a
  • 33:09significant decline in prisoners and
  • 33:12psychiatric inpatients as research
  • 33:15subjects in RCT's reflecting a
  • 33:18shift in thinking among researchers
  • 33:21that vulnerable populations needed
  • 33:24to be protected and could not just
  • 33:27be relied upon and exploited,
  • 33:31particularly given their vulnerability
  • 33:33relative to the broader population.
  • 33:37So simultaneously the civil rights movement
  • 33:40was also motivating new regulations,
  • 33:43protecting minorities in research.
  • 33:46So in 1965 we saw new policies resulting
  • 33:52from the 1964 Civil Rights Act,
  • 33:54so that no person in the United
  • 33:57States on the grounds of race,
  • 33:59color, or national origin could
  • 34:01be excluded from participation in,
  • 34:03denied the benefits of or subjected
  • 34:05to discrimination under any.
  • 34:07Program or activity.
  • 34:09Receiving federal financial
  • 34:10assistance and this required,
  • 34:12therefore,
  • 34:13that grant and award programs of
  • 34:16the Public Health service.
  • 34:18Would operate in compliance with
  • 34:20civil rights laws,
  • 34:21so this was a significant moment in
  • 34:24the history of a trial ethics and
  • 34:28protections of research subjects because.
  • 34:31At this time,
  • 34:32the United States was the leading funder
  • 34:34of clinical trials around the world,
  • 34:37and the attention to nondiscrimination
  • 34:42was having a significant impact
  • 34:45on the overall norms of research.
  • 34:49First affecting trends in trials
  • 34:51that were funded by the government,
  • 34:53but then also having a ripple effect
  • 34:57on trials conducted by other funding
  • 35:00entities who started to follow
  • 35:02a new scientific norm.
  • 35:04We also saw an eye NIH grant request
  • 35:09for proposals shifting to have
  • 35:12basic civil rights requirements of
  • 35:15occurring in non segregated facilities,
  • 35:19but this was all really insufficient
  • 35:22with regard to addressing the influence
  • 35:25of racism on scientific research,
  • 35:28and this became very clear when
  • 35:31the Tuskegee syphilis experiment
  • 35:33became public and this was.
  • 35:35Again,
  • 35:35another watershed moment for
  • 35:36the field of bioethics,
  • 35:38so we all know that antibiotics were
  • 35:41first used to treat syphilis in 1943.
  • 35:44However, in 1972,
  • 35:47Tuskegee was exposed as the
  • 35:51US Public Health service,
  • 35:52studying individuals for 40 years for
  • 35:55the natural progression of the disease,
  • 35:57despite treatment being available and
  • 36:01the sort of ethical justification
  • 36:03that the scientists.
  • 36:05Of the Tuskegee study made
  • 36:07for themselves was a very
  • 36:09utilitarian arguments.
  • 36:11They felt that because the
  • 36:13populations that they were studying
  • 36:15didn't have access to medical care,
  • 36:18it was appropriate for them to study
  • 36:21this population because they were
  • 36:24following the existing standard of care
  • 36:27that this population would be receiving
  • 36:31and not having access to to treatment.
  • 36:35Not having access to to health insurance,
  • 36:38but of course society felt very
  • 36:41differently about this and felt
  • 36:44that we should be holding our health
  • 36:47researchers to the standard of
  • 36:49treatment that is generally practiced
  • 36:51within medicine and not discriminating
  • 36:54against research participants who are
  • 36:57low income and taking advantage of
  • 37:00their lack of access to care in order
  • 37:03to exploit them for for research.
  • 37:05Purpose is preventing access to treatment
  • 37:08that that others in society are receiving.
  • 37:12But this is a trend that has not gone
  • 37:15away and will talk about even in recent
  • 37:18years in relation to the COVID-19 trials.
  • 37:21So the ethics response to Tuskegee
  • 37:23was first the 1972 creation of what?
  • 37:25What is now the Office for Human Research
  • 37:28protections in DHS and then in 1974,
  • 37:31the US Department of Health and
  • 37:33Human Services passed Title 45 code
  • 37:35of federal regulations per 46,
  • 37:37creating the requirement for
  • 37:39institutional review boards.
  • 37:41Then you can see here.
  • 37:44Two senators,
  • 37:45Mondale and Kennedy,
  • 37:46who were particularly instrumental
  • 37:49in creating these institutional
  • 37:52policies in 1974.
  • 37:53They helped to pass the
  • 37:55National Research Act,
  • 37:57creating the National Commission for
  • 37:58the Protection of Human Subjects of
  • 38:01Biomedical and Behavioral research,
  • 38:02and then also at an international level.
  • 38:05In 1975,
  • 38:06the World Medical Association
  • 38:08made its first revision to the
  • 38:10Declaration of Helsinki in Tokyo.
  • 38:13So in 1978,
  • 38:15the National Commission for the
  • 38:17Protection of Human Subjects of Biomedical
  • 38:20and Behavioral research created the
  • 38:22Belmont report and after many years,
  • 38:24four years of meeting at
  • 38:26the Belmont Retreat Center,
  • 38:28this group of leading bioethical
  • 38:32thinkers had deliberated.
  • 38:34What government policies should
  • 38:36look like with regard to the
  • 38:39guidelines for institutional review
  • 38:42boards and they considered.
  • 38:44At length,
  • 38:45whether they should promote very
  • 38:48detailed guidelines and they ultimately
  • 38:50came down to some very core simple
  • 38:53principles that could be broadly and
  • 38:56generally applied because they felt
  • 38:58like it was inappropriate to try
  • 39:02to specifically prescribe specific
  • 39:05research ethics for what they could
  • 39:08not necessarily predict would be a
  • 39:10number of different studies scenarios,
  • 39:12and rather it was more appropriate.
  • 39:14We have a broad set of general principles
  • 39:17that should be considered in every context,
  • 39:21regardless of of the variations
  • 39:23that that can occur,
  • 39:26so these principles included respect
  • 39:28for persons that we should protect.
  • 39:30All people with voluntary and informed
  • 39:33consent that researchers must be truthful.
  • 39:35There should be no deception that we
  • 39:38should protect those whose decision
  • 39:41capacities are limited and you
  • 39:43can see in this language a direct
  • 39:45reaction to the Tuskegee study.
  • 39:47That researchers must be truthful
  • 39:49that there should be no deception.
  • 39:51This is really the reverse of what
  • 39:54the Tuskegee researchers had done,
  • 39:56and so we could see historically the
  • 40:00alignment of developments in
  • 40:02the civil rights movement.
  • 40:04Having a direct influence on
  • 40:07our development of bioethical
  • 40:09regulations for clinical trials.
  • 40:11So the next principle that they developed
  • 40:14was beneficence doing no harm maximizing.
  • 40:17The benefits and minimizing the
  • 40:19risks to the research subjects.
  • 40:21Third, the principle of justice that
  • 40:23burdens and benefits of research should
  • 40:26be distributed fairly and equally.
  • 40:28Again, this was really a direct
  • 40:32response to Tuskegee because that
  • 40:35was a very clear case in which the
  • 40:38burdens and benefits of research were
  • 40:41not distributed fairly and equally.
  • 40:44So in response to the creation
  • 40:48of the Belmont report and all of
  • 40:52the bioethical regulations that
  • 40:54we saw come out of tuskeegee,
  • 40:57we saw a real significant rise in reference
  • 41:02to institutional review boards being
  • 41:05consulted for RCT's that were published.
  • 41:09However, we've also seen some substantial
  • 41:13and meaningful critiques of this
  • 41:16historical process of development.
  • 41:19So, for example,
  • 41:20Patricia King has written
  • 41:22in American bioethics,
  • 41:23individualism, self-determination,
  • 41:24and autonomy are paramount,
  • 41:27paramount, other values,
  • 41:28and other ethical issues have historically
  • 41:31enjoyed lesser status even today.
  • 41:33The failure to obtain informed consent
  • 41:35of the Tuskegee subjects continues
  • 41:37to receive greater attention.
  • 41:39And the social and economic conditions
  • 41:41in which the subjects found themselves,
  • 41:44which is a really critical entrenchment
  • 41:47observation that will carry forward,
  • 41:50as we're looking at the problems that
  • 41:53have recurred again and again with
  • 41:56regard to social and economic conditions,
  • 41:58leading to desperate research,
  • 42:01treatment overtime.
  • 42:02Susan Reverby that as the ethicist and
  • 42:04historian has also written that we need
  • 42:06to avoid just thinking about a simple,
  • 42:08good and evil while we pretend that
  • 42:11the structural factors that create
  • 42:13problems in the 1st place can be ignored.
  • 42:18So this brings us up to the more recent
  • 42:21history of advances in bioethics,
  • 42:25and we've seen a greater attention recently
  • 42:28to diversity and inclusiveness, so.
  • 42:32Following this period in the
  • 42:35late 1970s and into the 1980s,
  • 42:38when there was a concern about
  • 42:41exploitation of minorities in research,
  • 42:44we saw a shift in our public health
  • 42:47systems leadership so that more
  • 42:50women and minorities were taking
  • 42:53positions of leadership in the NIH,
  • 42:56and the FDA and within Congress.
  • 43:00And really this professional transition.
  • 43:04Lead to greater discussion,
  • 43:07not just of nondiscrimination,
  • 43:10but also of inclusion in research
  • 43:13so that throughout the 1980s
  • 43:15a series of working groups and
  • 43:19conversations were held about what
  • 43:21would make sense at a policy level,
  • 43:24not just with regard to non discrimination,
  • 43:26but with regard to having research
  • 43:29reflect the broader population so
  • 43:32that researchers were becoming.
  • 43:35Very aware of the trends toward white
  • 43:39men being studied more frequently than
  • 43:42they were members of the population,
  • 43:45and so by the early 1990s,
  • 43:48NIH funded RCT's were then required
  • 43:51to include people of different
  • 43:53ethnic and racial backgrounds.
  • 43:56Women, children, and the elderly,
  • 43:59and this was really a result of the work
  • 44:02of women and minorities drawing attention.
  • 44:05To these issues at a governmental level
  • 44:08so that the NIH Revitalization Act of
  • 44:121993 institutionalized the expectation
  • 44:14that these populations be included in
  • 44:18trials that were funded by the government,
  • 44:21and then the FDA soon followed suit
  • 44:24by also requiring that drug sponsors
  • 44:27of trials include diverse populations
  • 44:30in order to obtain drug approval.
  • 44:34This was also a time when
  • 44:38scientifically thinking shifted so that.
  • 44:42Inclusiveness of diverse populations was
  • 44:44not just seen as ethically appropriate.
  • 44:47It was also seen as scientifically
  • 44:51more rigorous and race and other
  • 44:56demographic backgrounds started to be
  • 44:59included in study design in order to
  • 45:03make our scientific findings more useful.
  • 45:08So we stopped shifts overtime with
  • 45:11increasing discussion of defining
  • 45:14the race of trial subjects.
  • 45:16You see, there was a spike in attention.
  • 45:19Uh,
  • 45:20aligning with the the civil rights
  • 45:23movement and then in more recent years
  • 45:26we saw a significant rise in in at
  • 45:29least defining the race of trial subjects.
  • 45:31But we can talk in the Q&A about
  • 45:35the significant limitations of
  • 45:37the existing regulatory structure
  • 45:39with regard to trial diversity.
  • 45:42You can see here there was also
  • 45:45an increased attention overtime
  • 45:47to enrolling pregnant women and
  • 45:50considering the myriad ethical
  • 45:53dimensions of that in clinical research.
  • 45:57But the past several decades
  • 46:00have really given us a lot more
  • 46:03thought and attention to issues of
  • 46:06participant participant diversity.
  • 46:08From an ethical perspective.
  • 46:10We've also seen a recent issues
  • 46:13with regard to child globalization,
  • 46:16so global RCT policies to
  • 46:19the extent that they exist,
  • 46:21tend to reflect competing interests.
  • 46:24The International Council for
  • 46:26Harmonization was created in 1992,
  • 46:29attempt to regulate basic standards
  • 46:34of drug trials around the world,
  • 46:37but this is really been critiqued
  • 46:39for having an industry focused and
  • 46:41also for its non inclusiveness.
  • 46:43Of diverse populations around
  • 46:45the world at a policy making
  • 46:48level, this has started to
  • 46:51shift in more recent years,
  • 46:53but as we've seen this trend toward
  • 46:57clinical trials being conducted globally,
  • 47:00the issues of patient protections
  • 47:02and human diversity take on new
  • 47:06valences that require attention at a
  • 47:08policymaking level that really has
  • 47:11not been sufficiently addressed.
  • 47:13And unfortunately,
  • 47:14history is tended to repeat itself,
  • 47:18so as trials have globalized
  • 47:20social inequalities continue to
  • 47:22have ramifications for our cities.
  • 47:24For example,
  • 47:25there were the scenarios of the ACTH
  • 47:29HIV trials in which participants in Sub
  • 47:33Saharan Africa were allocated to a placebo,
  • 47:37whereas participants in
  • 47:39developed settings were not,
  • 47:42and this received significant.
  • 47:44Ethical debate and criticism for
  • 47:47repeating the same assumptions that
  • 47:50had occurred in the Tuskegee study,
  • 47:53which is that the existing standard
  • 47:55of care of lack of access was used
  • 47:59to justify studying participants by
  • 48:02not providing the standard of care
  • 48:04for medicine that existed elsewhere.
  • 48:07We've also seen contract research
  • 48:09organizations a multibillion dollar
  • 48:11annual industry being critiqued for
  • 48:14targeting middle income countries,
  • 48:15often with ethnically homogeneous
  • 48:18populations.
  • 48:19Looser regulatory oversight,
  • 48:20sneaker systems, ethical review.
  • 48:24And as a result of this we've seen
  • 48:28patient interchangeability questions
  • 48:29so that we're asking frequently.
  • 48:31Now,
  • 48:32are the populations being studied in
  • 48:35our clinical trials internationally,
  • 48:37really reflecting the ultimate consumers
  • 48:40of the products that are being tested?
  • 48:44This has also raised questions
  • 48:46of post trial treatment,
  • 48:47access to interventions that
  • 48:50are being tested in populations.
  • 48:54Globally and this has really come
  • 48:57into public awareness again recently
  • 49:00with the COVID vaccine trials.
  • 49:02So despite hosting a clinical
  • 49:04trial of the Astra Zeneca vaccine,
  • 49:06South Africa was unable to secure
  • 49:08a fair pricing agreement for
  • 49:10vaccines quite recently,
  • 49:12and the country procured its first million
  • 49:15doses of the vaccine at $5.25 per dose,
  • 49:19more than double the
  • 49:23$2.60 per dose.
  • 49:24Paid by the European Union countries
  • 49:27to this same company and so we've
  • 49:30seen this significant concern being
  • 49:33raised at an international level
  • 49:36with regard to the individuals who
  • 49:39are being tested in clinical trials,
  • 49:42not necessarily being treated fairly
  • 49:46and having access to the products
  • 49:49that are are being tested on them
  • 49:53during the course of a study.
  • 49:54Once that study is completed.
  • 49:57So I'd like to close by
  • 50:00highlighting some key findings.
  • 50:03First trial design study location ethical
  • 50:06safeguards for research subjects.
  • 50:08Participant diversity investigator,
  • 50:09accountability,
  • 50:10and even the likelihood of favorable
  • 50:13trial results have all been
  • 50:15historically influenced by social,
  • 50:16political, and economic context.
  • 50:18Ongoing trends in RCTs indicate
  • 50:21that intellectual developments have
  • 50:23tended to be insufficient alone to
  • 50:27change normative research practices.
  • 50:30We've seen this over and over again where?
  • 50:33Scientific advances have been
  • 50:35adopted by those who are interested.
  • 50:39Ethical developments have been
  • 50:41incorporated into the research of those
  • 50:44who value those at the goal developments,
  • 50:47but without some sort of
  • 50:50regulatory infrastructure,
  • 50:51there hasn't been a normative shift
  • 50:54toward overall embrace of scientific
  • 50:58and ethical standards that have
  • 51:02arguably been necessary to have.
  • 51:04Optimal and ethical science.
  • 51:07However,
  • 51:08once precedents are established through
  • 51:11the leadership of regulators and through
  • 51:15the leadership of funding agencies,
  • 51:18there have tended to be cultural
  • 51:20shifts in research ethics that have
  • 51:22perpetuated and become normative.
  • 51:24So we've seen this,
  • 51:25for example,
  • 51:26with the development of the Declaration
  • 51:30of Helsinki being incorporated
  • 51:32into regulatory structures.
  • 51:34And the leading drug developing
  • 51:37locations around the world first
  • 51:40and then being adopted by countries
  • 51:43that were following suit of of
  • 51:47leading regulators internationally.
  • 51:49So at once informed consent started
  • 51:53to be required by some countries.
  • 51:55It started to be increasingly required by
  • 51:59others as a sort of normative standard.
  • 52:04Finally,
  • 52:04as new challenges emerge,
  • 52:05history is provided examples of
  • 52:07how science has been dramatically
  • 52:10transformed through the work of
  • 52:12individuals committed to ethics
  • 52:13and scientific integrity over
  • 52:15other competing interests.
  • 52:17So we've seen a lot of recurring
  • 52:20problematic themes overtime,
  • 52:21but I'd also like to end on this
  • 52:24point of optimism that we've
  • 52:27seen some really significant.
  • 52:29Game changing.
  • 52:32Work coming from individuals who have
  • 52:35been committed to scientific rigor
  • 52:38and to ethical standards that have
  • 52:41led to major changes in improving
  • 52:43the quality of science and the
  • 52:46quality of ethics for the broader
  • 52:48population and so moving forward,
  • 52:51I would like to think that we can
  • 52:53learn from history in this regard as
  • 52:56well that it is quite possible for
  • 52:59committed individuals who are determined.
  • 53:02To change the way that research,
  • 53:05ethics and their overall
  • 53:08research process operate,
  • 53:10but you know it,
  • 53:12it takes time and it takes political
  • 53:16will and support as well.
  • 53:18So that's a sort of broad overview
  • 53:21of this history,
  • 53:22and I I look forward very much to
  • 53:25discussing with you all whatever
  • 53:28is of interest within this.
  • 53:32Thank you so much Laura.
  • 53:33That was outstanding. Water.
  • 53:34Wonderful review. I learned a lot.
  • 53:36I'm sure most folks on the call did.
  • 53:39I would invite you all now folks if you
  • 53:41have questions or comments to put him
  • 53:43through the the Q&A function on zoom,
  • 53:45and I will just take something,
  • 53:47take a quick one while while some
  • 53:48questions go in there, Laura,
  • 53:50it was interesting when you.
  • 53:53You commented on the the I saw President
  • 53:55Kennedy signing up signing the law
  • 53:57when when it became federal law in
  • 53:59the United States about regarding
  • 54:01informed consent for these trials and
  • 54:03about the end of Tuskegee and and the
  • 54:07progress has been made ethically.
  • 54:10And it it struck me and I,
  • 54:12I think that you this was perhaps
  • 54:14part of your message is that that it
  • 54:17really wasn't the medical or academic
  • 54:20community that finally had to say, listen,
  • 54:24the way we've been doing about this.
  • 54:25And of course,
  • 54:26it wasn't just testing the way we've
  • 54:27been going about clinical research,
  • 54:29human subjects,
  • 54:30the absence of really good human subjects
  • 54:33protection is really not appropriate.
  • 54:36This is really not good.
  • 54:37We need some stricter rules that
  • 54:39I get the sense that this.
  • 54:40It really didn't happen at the.
  • 54:44This really wasn't brought about so
  • 54:46much by either medicine or academia,
  • 54:47but really more by the public when it
  • 54:49went when it published the New York Times.
  • 54:51Is that a fair assessment?
  • 54:53Yeah, I think so.
  • 54:55You know there's been some really nice
  • 54:59scholarship on how this transition
  • 55:02occurred and behind the scenes,
  • 55:04which I wasn't able to cover in this talk.
  • 55:07There was also.
  • 55:09A significant effort over the
  • 55:11decade prior to the fiber Harris
  • 55:15amendments in which senators
  • 55:17could favor and Harris had tried
  • 55:20to reform the FDA unsuccessfully,
  • 55:22and so sadly,
  • 55:23what seems to have been a trend
  • 55:26in the history of bioethics
  • 55:28is that it took the public,
  • 55:31becoming aware of a huge violation of
  • 55:36patient rights and giving that public.
  • 55:41Outcry having having that provide
  • 55:46impetus to the policymakers to
  • 55:48actually carry out the objectives that
  • 55:51they had been hoping to carry out.
  • 55:54That's I think not to say that it
  • 55:58isn't possible for change to happen
  • 56:01without a crisis, but there was.
  • 56:06In this case, and in a number of cases,
  • 56:08historically a conglomeration of effects
  • 56:12where public outcry and political will.
  • 56:18All moved toward making shifts that,
  • 56:21as you point out,
  • 56:22we're not really being made by
  • 56:25the scientific community itself,
  • 56:27and I think we're in a moment
  • 56:29now historically as well.
  • 56:30Where we have some major crises
  • 56:33of public trust in science
  • 56:36with regard to drug profits,
  • 56:39and you know the recurring issues of
  • 56:42who is being tested in our in our trials
  • 56:45and their access to treatments where.
  • 56:49There there is sufficient public
  • 56:52concern and you know the question
  • 56:55is whether we can find the leaders
  • 56:58to make the changes at a policy
  • 57:01level that we've seen historically.
  • 57:02Because we're now in a in a period
  • 57:04that is much more challenging from a
  • 57:07global perspective where we need to
  • 57:09see some sort of international standards
  • 57:11implemented at a national level.
  • 57:14But that takes a lot of first
  • 57:17international agreement for
  • 57:18what those standards are.
  • 57:19And then advocacy at a national level,
  • 57:23from from policymakers to
  • 57:25to implement those changes.
  • 57:28Sometimes, perhaps in addition to the
  • 57:31political will and the leadership.
  • 57:34Again, I think the fact that the
  • 57:36that the that we sometimes require
  • 57:38public scrutiny before we kind of
  • 57:40come to our senses as a profession.
  • 57:43I had a boss years ago when I worked New
  • 57:45London, used to talk about the New London
  • 57:46Day rule that was the paper out this.
  • 57:48We call it the New Haven Register
  • 57:49rule or the New York Times rule.
  • 57:51Her basic rule was she says, you know,
  • 57:53if you wouldn't want to see it
  • 57:55on the front page of the paper.
  • 57:56You got to think very carefully
  • 57:57before you do it and or make it a
  • 57:59policy for what we do in this House.
  • 58:01Is it is that there are so many
  • 58:03things at once.
  • 58:04Once there's been a light shined on them,
  • 58:06people realize now we really
  • 58:07can't be doing that.
  • 58:09I'd like to think and hope that we
  • 58:10can kind of be a step ahead of that.
  • 58:11But of course one of the things about.
  • 58:13About these meetings and and getting
  • 58:15scholars like you to speak to us is
  • 58:17that there are many scholars and members
  • 58:18of the health care in the audience.
  • 58:20But there's also members of
  • 58:21the public in the audience,
  • 58:22so all of us are hearing and benefiting from
  • 58:25from your wisdom here, Doctor Bothwell.
  • 58:27Now I have some questions please.
  • 58:30The statistical work that you
  • 58:33referred to early on.
  • 58:34Sir Hills work.
  • 58:35Was someone asked how does the
  • 58:37statistical work of Florence Nightingale
  • 58:39fit in you familiar with that at all,
  • 58:41or?
  • 58:42Yeah it's very funny 'cause I
  • 58:44was preparing for this talk.
  • 58:46I was thinking about I visited.
  • 58:51The British National Archives and.
  • 58:56Actually held some documents by Florence
  • 58:58Nightingale in her in her penmanship,
  • 59:01which was an incredible experience
  • 59:04looking at her thinking on on statistics,
  • 59:08and I think that there's
  • 59:12room for scholarship too.
  • 59:14Better describe the contributions that
  • 59:17she's made into this sort of evolution of
  • 59:21of thought and clinical trial history,
  • 59:24but certainly she Tran she was a part
  • 59:27of that transition from thinking about
  • 59:29patients on an individual level to
  • 59:32thinking about science more in medicine,
  • 59:36more systematically that you know
  • 59:39was occurring in the in the sort of
  • 59:42thought transition toward the modern.
  • 59:44Era, but I I think that that's a
  • 59:47that's a really important point
  • 59:50to raise for contributions.
  • 59:52Thank you, could you say something
  • 59:55about the historical development and
  • 59:57ethical concerns that have arisen in
  • 59:59the social and behavioral sciences,
  • 01:00:01including psychology and psychiatry,
  • 01:00:02about the historical development
  • 01:00:04and the ethical concerns,
  • 01:00:06psychology and psychiatry?
  • 01:00:07Have you have you seen something specific
  • 01:00:09about that that you could speak to?
  • 01:00:12Yeah, I love that question because
  • 01:00:16actually I've looked at, you know,
  • 01:00:18thousands of trials now overtime
  • 01:00:20and there was this period when
  • 01:00:22antipsychotics were being developed
  • 01:00:24in the 1950s and being tested in
  • 01:00:28early RCTs on populations who
  • 01:00:32are considered now vulnerable,
  • 01:00:35but they were being widely tested
  • 01:00:39on institutionalized populations,
  • 01:00:40oftentimes without.
  • 01:00:42Consent and without even any real
  • 01:00:45awareness on the parts of the researchers
  • 01:00:49that they were engaging in research
  • 01:00:51with with a set of vulnerable subjects.
  • 01:00:55In a post Second World War period.
  • 01:00:59Psychiatric and research and antipsychotics
  • 01:01:02were one of the leading areas in
  • 01:01:05which RCT's were being conducted,
  • 01:01:08and so I think this is a fairly
  • 01:01:12unfortunate period historically
  • 01:01:14when it was after the development
  • 01:01:17of the scientific methods of RCTs,
  • 01:01:19but before the implementation
  • 01:01:22of bioethical protections for
  • 01:01:24patient populations,
  • 01:01:25and there was a lot of research done in this.
  • 01:01:29Period when we saw this emergence
  • 01:01:31of a broad range of antipsychotics.
  • 01:01:34And the the participants were were not
  • 01:01:37necessarily being treated as they as
  • 01:01:40we would like to to see them being treated,
  • 01:01:44and so that is shifted over time.
  • 01:01:47And we've realized that it's possible
  • 01:01:50to conduct research on patients in
  • 01:01:52a way that is bringing them into
  • 01:01:56the discussion and ensuring that
  • 01:01:58they want to be studied.
  • 01:02:00But there's certainly a
  • 01:02:02problematic history in that.
  • 01:02:04Field,
  • 01:02:05particularly in that period before
  • 01:02:08the Declaration of Helsinki
  • 01:02:10and the Belmont report.
  • 01:02:13Code of federal regulations.
  • 01:02:15You know 45.
  • 01:02:17So yeah, that's that's the you know.
  • 01:02:19It's it's.
  • 01:02:20It's a very interesting history.
  • 01:02:24Next question, some of estimated that
  • 01:02:26humans challenge trials and didn't
  • 01:02:28really refer it to refer to that during
  • 01:02:30your talk human challenge trials early
  • 01:02:32in the COVID pandemic could have
  • 01:02:34expedited vaccine development and
  • 01:02:36potentially saved millions of life years,
  • 01:02:39but historically is challenge trials
  • 01:02:41have been problematic, to say the least.
  • 01:02:43What are your thoughts on humans
  • 01:02:44and could you define for us that
  • 01:02:46whether you I assume this refers to
  • 01:02:48the deliberate deliberate exposure
  • 01:02:49of individuals to the disease?
  • 01:02:50What are your thoughts on human
  • 01:02:52challenge trials in Houston
  • 01:02:54pandemic? I love that question as well
  • 01:02:56because this has been a recurring
  • 01:02:59theme in the history of bioethics.
  • 01:03:01I mean, we have the modern field of
  • 01:03:04bioethics developing in the second
  • 01:03:05half of the 21st or the 20th century.
  • 01:03:07But prior to this point.
  • 01:03:11It was not uncommon for researchers
  • 01:03:14to expose themselves to diseases
  • 01:03:17and then test agents on themselves,
  • 01:03:20and I think there's some really
  • 01:03:24compelling ethical literature talking
  • 01:03:27about informed participation in
  • 01:03:30challenge trials being akin to.
  • 01:03:34Serving the public in other ways.
  • 01:03:37For example, firefighters,
  • 01:03:40police officers,
  • 01:03:42individuals who expose themselves to
  • 01:03:45risk and potential harm for the broader good.
  • 01:03:49I think the the most important
  • 01:03:51dimension of these trials,
  • 01:03:53of course,
  • 01:03:54is that individuals going into
  • 01:03:56them don't have an unrealistic idea
  • 01:03:59of the benefits and the risks of
  • 01:04:03of what they're being exposed to.
  • 01:04:07But should they be fully fully
  • 01:04:10aware and informed,
  • 01:04:12I personally find compelling the
  • 01:04:15arguments that compare these two
  • 01:04:18to other forms of public service.
  • 01:04:21But I know there's there's a range
  • 01:04:23of opinions on this well,
  • 01:04:24but I appreciate that,
  • 01:04:26but but the questioner,
  • 01:04:27and I've interested in your
  • 01:04:28thoughts or your thoughts have
  • 01:04:30the fully informed individual
  • 01:04:32that a properly designed study if
  • 01:04:34the subjects were fully informed.
  • 01:04:36You think that'll be
  • 01:04:38ethically acceptable? Informed
  • 01:04:39of the risks. I I know someone who
  • 01:04:41volunteered for Edge challenge trial
  • 01:04:43and was very proud of doing that.
  • 01:04:46Actually who was a low risk individual
  • 01:04:49who is willing to to be exposed and.
  • 01:04:54I I I I admired that individual.
  • 01:05:00But I don't think that we
  • 01:05:03should ever compel anybody.
  • 01:05:05Have to be extremely voluntary.
  • 01:05:07Family volunteer.
  • 01:05:09You know if we offer incentives.
  • 01:05:12I think I would be problematic
  • 01:05:14at the same time.
  • 01:05:15There's the argument that
  • 01:05:16individuals who do that deserve to
  • 01:05:19receive some sort of compensation,
  • 01:05:21but I think I think when you get
  • 01:05:22into the realm of of compelling
  • 01:05:24individuals to expose themselves
  • 01:05:26to potential harm using financial
  • 01:05:28means that that gets really funny.
  • 01:05:30Well, right,
  • 01:05:31they're they're in there in lies.
  • 01:05:32The problem with a certain
  • 01:05:33amount of coercion revenues.
  • 01:05:34If we see that that that that
  • 01:05:36individual deserve some compensation
  • 01:05:37for making that sacrifice.
  • 01:05:39Just like firemen get paid,
  • 01:05:41so we say that someone.
  • 01:05:42Does this deserve some compensation?
  • 01:05:44So this of course means that that if
  • 01:05:46the compensation if it's a if it's a
  • 01:05:49financial compensation that to a poor man,
  • 01:05:51that's a that's a very different
  • 01:05:53level of coercion than to a rich man.
  • 01:05:55And and so this is potentially problematic.
  • 01:05:58But I, but I hear you, Laura,
  • 01:06:00and I actually had a member of my
  • 01:06:01family who was young and strong,
  • 01:06:03and who said, well, you know,
  • 01:06:03let's try it on me.
  • 01:06:05Let's try it on me and my friends,
  • 01:06:06you know, let's let's do that at this thing.
  • 01:06:07Gonna kill my grandma.
  • 01:06:10So so that I I get the sense what
  • 01:06:12your sense is that under the right
  • 01:06:14circumstances this could be acceptable.
  • 01:06:16A follow up question to that question
  • 01:06:19was more generally there are other
  • 01:06:20other other changes we should
  • 01:06:22consider to speed the development of
  • 01:06:24new medications and interventions,
  • 01:06:26particularly lifesaving intervention.
  • 01:06:27So other things we should be considering.
  • 01:06:32Yeah, I think this is a great.
  • 01:06:35Question and it's an objective of of science
  • 01:06:37to speed the development of research.
  • 01:06:40I think the history of randomized
  • 01:06:43controlled trials has revealed
  • 01:06:45numerous scenarios in which we've
  • 01:06:48been too eager to develop new products
  • 01:06:52and not sufficiently tested them,
  • 01:06:54and then ultimately needed to remove them
  • 01:06:57from the market as a result of post approval,
  • 01:07:00adverse events becoming known.
  • 01:07:03So it's a really delicate balance.
  • 01:07:05I've written about.
  • 01:07:08You know different means
  • 01:07:10of of speeding trials,
  • 01:07:12and I think that history has shown us
  • 01:07:16that we really have to ensure trial rigor.
  • 01:07:21In order to advance our scientific progress,
  • 01:07:26otherwise sometimes we move so
  • 01:07:28quickly that we then have to go back
  • 01:07:31and and correct our mistakes, but.
  • 01:07:35There are a lot of arguments
  • 01:07:37being made about the regulatory
  • 01:07:40infrastructure slowing down the
  • 01:07:43process of developing new therapies.
  • 01:07:46Which. You know is is a concern.
  • 01:07:51At the same time,
  • 01:07:52if we compare our own Food
  • 01:07:54and Drug Administration,
  • 01:07:55for example to other regulatory
  • 01:07:58agencies internationally,
  • 01:07:59we actually have one of the
  • 01:08:02fastest org approval processes.
  • 01:08:04So it's it's a real delicate
  • 01:08:07balance in terms of speeding
  • 01:08:10delivery of of new therapies,
  • 01:08:12and then also ensuring that those
  • 01:08:14therapies are safe and effective.
  • 01:08:19Can you comment on the political
  • 01:08:21transition from concerns about bias
  • 01:08:23toward studying vulnerable minorities
  • 01:08:25to more recent concerns about bias
  • 01:08:28toward excluding vulnerable minorities?
  • 01:08:30Both are problematic, of course,
  • 01:08:32but is there a tension in this
  • 01:08:34pendulum that's often overlooked?
  • 01:08:38That's a really great question, so.
  • 01:08:43I think that there is there is a
  • 01:08:46tension in the pendulum and it often
  • 01:08:49comes out in the question of how do
  • 01:08:52we even measure diversity so you know
  • 01:08:57we saw this valuable transition from.
  • 01:09:02Major problems in our research on
  • 01:09:08drugs and different interventions
  • 01:09:09and even health outcomes outside
  • 01:09:12of clinical trials where we just
  • 01:09:14didn't have information on broad and
  • 01:09:17diverse populations and we were making
  • 01:09:20claims about therapies and women
  • 01:09:22that had only been studied in men,
  • 01:09:24sometimes, even when those therapies
  • 01:09:26were designed to treat women.
  • 01:09:28So we we have seen this shift.
  • 01:09:32To learn more.
  • 01:09:34You know, consider it treatment
  • 01:09:37of of broad populations.
  • 01:09:39But then we've seen major discussion
  • 01:09:42of how can we even measure something
  • 01:09:46like rates where it's many argue
  • 01:09:51in part a socially.
  • 01:09:55Articulated concept that reflects.
  • 01:10:00A wide range of of social factors
  • 01:10:03and race is also connected to social
  • 01:10:06determinants of health and a very
  • 01:10:09complex way and ethnicity can sometimes.
  • 01:10:13Correspond to other social determinants
  • 01:10:15of health and then changes in the social
  • 01:10:19determinants of health mean that those
  • 01:10:22ethnic variations could potentially change.
  • 01:10:25We've also seen some really great
  • 01:10:27research by David Williams.
  • 01:10:28For example, looking at the impact
  • 01:10:30of racism on health outcomes.
  • 01:10:32But we're in a stage now and looking at
  • 01:10:36diversity of clinical trial participants
  • 01:10:39that I think is quite inadequate.
  • 01:10:41We have.
  • 01:10:43Decades now of regulators developing policies
  • 01:10:46to try to promote inclusion in trials,
  • 01:10:50but then we don't have any significant
  • 01:10:53forms of accountability to statistical
  • 01:10:56significance of what we find or a very clear
  • 01:11:00sense of how we define different categories,
  • 01:11:03particularly for race,
  • 01:11:05race and ethnicity.
  • 01:11:08And and even within that,
  • 01:11:10particularly for multiracial individuals
  • 01:11:13and people from different backgrounds.
  • 01:11:16So typically,
  • 01:11:17when you look at the trials that are
  • 01:11:20approved by the FDA for new therapies,
  • 01:11:23they they'll measure race and
  • 01:11:26ethnicity and other variables
  • 01:11:29but beyond male and female sex,
  • 01:11:33typically you see frequent claims that
  • 01:11:36there is not statistical significance.
  • 01:11:39To support.
  • 01:11:41Any significant outcomes in terms of.
  • 01:11:47Saying there's from one group to the next,
  • 01:11:50even though oftentimes they
  • 01:11:52measure differences that should
  • 01:11:53they have broader populations,
  • 01:11:55they might be able to find
  • 01:11:57something statistically significant,
  • 01:11:59so I think that there's a place
  • 01:12:02right now for post approval.
  • 01:12:04Pharmaco epidemiological research
  • 01:12:06that is looking at trends out of broad
  • 01:12:11population level of interventions by race,
  • 01:12:15ethnicity and different.
  • 01:12:18Demographic backgrounds that can hopefully
  • 01:12:20help to better inform the science.
  • 01:12:25But that's just one dimension,
  • 01:12:27and I think that the question is
  • 01:12:30also getting at what is fair,
  • 01:12:32right from an ethical standpoint.
  • 01:12:35So the question of exclusion to the
  • 01:12:39question of inclusion then also
  • 01:12:41makes us think about how can we
  • 01:12:44make that inclusion process fair,
  • 01:12:47and you know appropriate in how we're
  • 01:12:51we're drawing populations into our studies,
  • 01:12:55particularly when we see trials.
  • 01:12:57Being conducted in multinational settings,
  • 01:13:00you know how can the the diversity
  • 01:13:04categories really truly represent the
  • 01:13:06broad populations of the world who
  • 01:13:08will be consuming a product and then?
  • 01:13:11Also how can we ensure that the
  • 01:13:14individuals that we are using in
  • 01:13:16our studies as proxies for race and
  • 01:13:18ethnicity were drawn into the studies
  • 01:13:20in a way that is fair and you know,
  • 01:13:25not tokenistic and also.
  • 01:13:28Not repeating scenarios of the past
  • 01:13:32where people of diverse backgrounds
  • 01:13:35have been relied upon to produce
  • 01:13:39study results that are not then
  • 01:13:42informing medical treatment in
  • 01:13:44their local communities so.
  • 01:13:46I, I think a lot of the issues that
  • 01:13:49we face historically were still we're
  • 01:13:51still grappling with today because
  • 01:13:53we haven't seen the next phase of
  • 01:13:56ethical development from a regulatory
  • 01:13:59perspective with regard to clinical trials.
  • 01:14:03Thank you given the experience
  • 01:14:04of black people in Tuskegee,
  • 01:14:06how would you enhance the
  • 01:14:08participation of black people in
  • 01:14:10randomized controlled trials today?
  • 01:14:14So I think the. The issue you know with
  • 01:14:19Tuskegee was of course most importantly
  • 01:14:23with deception and not offering the
  • 01:14:26existing standard of care to the community.
  • 01:14:30But I think what we see over and over
  • 01:14:33again is that this trend recurs, and I,
  • 01:14:37I think that there there was a really
  • 01:14:39powerful debate in the New England
  • 01:14:41Journal of Medicine in the early 90s,
  • 01:14:45in which really respected ethicists
  • 01:14:47on both sides of the debate.
  • 01:14:49We're making arguments for and against
  • 01:14:52having a placebo in the AZT trials.
  • 01:14:56I think bio ethical thinking
  • 01:14:58has tended to shift since then,
  • 01:15:01so that there is a general.
  • 01:15:05Discussion in a lot of the international
  • 01:15:09policies that are being made that
  • 01:15:12state that we need to offer post trial
  • 01:15:15access to care for all populations
  • 01:15:17who are participating in trials.
  • 01:15:21But the problem is that we see
  • 01:15:24the United Nations, the WHL,
  • 01:15:26different that icah different
  • 01:15:28organizations coming up with
  • 01:15:30statements that this should be done.
  • 01:15:32But then we don't see
  • 01:15:34any regulatory policies.
  • 01:15:35Requiring that that we
  • 01:15:37ensure post trial access,
  • 01:15:39I think we've done a better job
  • 01:15:42of avoiding deception in trials
  • 01:15:45and having informed consent,
  • 01:15:46but even there,
  • 01:15:48you know there's some great thinking
  • 01:15:50coming out of Yale in terms of asking.
  • 01:15:53Is informed consent always truly
  • 01:15:56informed and how are we ensuring
  • 01:15:59that participants aren't simply
  • 01:16:01signing a very lengthy document,
  • 01:16:04but they're being made fully
  • 01:16:06aware of the scientific process?
  • 01:16:09The way that we are developing knowledge
  • 01:16:13and the true risks and benefits of
  • 01:16:16of what they're being exposed to.
  • 01:16:19In this study, so you know,
  • 01:16:21I, I think in terms of.
  • 01:16:25Populations who have been subjected
  • 01:16:28to racism by medical practitioners.
  • 01:16:32There's definitely a lot of room
  • 01:16:36for improvement with regard to.
  • 01:16:38Building up trust and having full
  • 01:16:43accountability for for researchers for
  • 01:16:46distributing the benefits of their research,
  • 01:16:48but then also for ensuring that
  • 01:16:53participants in trials are having you know,
  • 01:16:58a sufficient discussion of risks
  • 01:17:01and benefits that that will allow
  • 01:17:03them to be truly informed decisions.
  • 01:17:05And this this applies of course across.
  • 01:17:08Populations, but as a result of teskey,
  • 01:17:12there's been a significant distrust.
  • 01:17:17In the medical community that is has
  • 01:17:20emerged within African American communities,
  • 01:17:23which is quite understandable
  • 01:17:25and his you know,
  • 01:17:27also been the subject of some really
  • 01:17:29useful ethical discussion in terms of how
  • 01:17:32to rebuild that trust and have you know,
  • 01:17:37fair and appropriate dynamics.
  • 01:17:39We at the School of Public Health have
  • 01:17:42Doctor Angela Parrott who teaches on
  • 01:17:45the subject of racism and health.
  • 01:17:47Has done some really useful work on
  • 01:17:51community engagement and talking about,
  • 01:17:54you know,
  • 01:17:55participate in community engagement
  • 01:17:57and participatory research where
  • 01:17:59community members are paid for
  • 01:18:01their time to consult and inform.
  • 01:18:03Research that is done on them,
  • 01:18:06and I think that's really the
  • 01:18:07direction that we need to be taking
  • 01:18:10our clinical research overtime and
  • 01:18:12to make sure that you know we're
  • 01:18:15we're whoever we're studying that.
  • 01:18:18Representatives of that community
  • 01:18:20are brought into the process
  • 01:18:22of of conducting the research.
  • 01:18:26Thank you.
  • 01:18:28A comedy which I wish I will share.
  • 01:18:31Thank you for informative talk.
  • 01:18:33Its share of a large university IRB.
  • 01:18:35I'm aware that European standards
  • 01:18:37for research are much stronger.
  • 01:18:38Incidentally, I'm a psychiatrist and
  • 01:18:40clinician and keenly aware of how
  • 01:18:42vulnerable patients can be at risk.
  • 01:18:44I urge IRB's to consider
  • 01:18:46social determinants of health.
  • 01:18:47Also present risks and widens the group
  • 01:18:50of so-called vulnerable participants.
  • 01:18:57A direct a direct a simple question if
  • 01:19:00if an organization seeks to perform
  • 01:19:03a clinical trial in a country that's
  • 01:19:07an impoverished country and says,
  • 01:19:09well, we are going to bring this
  • 01:19:10drug and you talked about the
  • 01:19:12post trial availability of drugs,
  • 01:19:14what would be the answer to recognizing that?
  • 01:19:16That seems to be the accepted standard?
  • 01:19:18What's the direct response?
  • 01:19:19If if a pharmaceutical company says
  • 01:19:21we're going to go into this country
  • 01:19:23and we're going to trial this now,
  • 01:19:25this there is no treatment
  • 01:19:26available right now.
  • 01:19:27Of this population, wherever it is,
  • 01:19:29if we bring this drug in here and
  • 01:19:31we do a randomized control trial,
  • 01:19:3350% of the people are going
  • 01:19:35to have access to this.
  • 01:19:36If we don't,
  • 01:19:36zero percent are going to have access to it.
  • 01:19:38That population that we study.
  • 01:19:40So therefore we're doing net
  • 01:19:42good by bringing this here,
  • 01:19:45even if we don't make it available
  • 01:19:46to everybody after the trial.
  • 01:19:47If it's shown to be effective,
  • 01:19:49what would be the response to that?
  • 01:19:51I've seen a trend in a lot of the
  • 01:19:55leading ethicists in this area moving
  • 01:19:58towards some sort of standard of an
  • 01:20:01expectation for post trial access.
  • 01:20:03Of course, you can't realistically provide.
  • 01:20:08Interminable post trial access
  • 01:20:10for a population because that's
  • 01:20:13not financially feasible,
  • 01:20:15but at least conducting a study
  • 01:20:19on a population should not
  • 01:20:21simply end the moment the trial.
  • 01:20:24And but there should be some
  • 01:20:28benefit for some period of time.
  • 01:20:31Month, years after the completion of a trial.
  • 01:20:36So that.
  • 01:20:37People living in that population can
  • 01:20:40still have access to the treatment,
  • 01:20:43particularly trial participants,
  • 01:20:44so that they can have continued
  • 01:20:47access to the treatment that they
  • 01:20:48were exposed to in the trial,
  • 01:20:50particularly should improve
  • 01:20:51beneficial to them,
  • 01:20:52but also having some period
  • 01:20:56of access for the community.
  • 01:20:59There has been an argument
  • 01:21:00that that is a sort of.
  • 01:21:02Social obligation.
  • 01:21:04I think that those arguments have
  • 01:21:07been fairly ethically compelling.
  • 01:21:10The exact amount of what is offered,
  • 01:21:13I think, is of course.
  • 01:21:15Relative to what is being studied,
  • 01:21:18the profits of that intervention there.
  • 01:21:20There's so many dynamics that would
  • 01:21:22go into figuring out what is fair,
  • 01:21:24but simply going in and testing and
  • 01:21:28intervention and then leaving I.
  • 01:21:30I think that there's there's been
  • 01:21:32a shift among ethicists that that
  • 01:21:34just doesn't seem quite right.
  • 01:21:36We have to do a little bit better than that.
  • 01:21:39Well, I I, I agree, but I but now
  • 01:21:41I gotta find you don't know about
  • 01:21:42anymore but I got a very wealthy
  • 01:21:45pharmaceutical company that I that I
  • 01:21:46also run in my spare time and I say,
  • 01:21:48well, you know if you say
  • 01:21:49there's a social responsibility.
  • 01:21:51So if I say well, why should I have
  • 01:21:53more of that social responsibility?
  • 01:21:54I'm gonna go in there.
  • 01:21:55Make this drug available to half the
  • 01:21:57people running around in my eyes
  • 01:21:59this we're going to do this we're
  • 01:22:00going to get out now why do I have
  • 01:22:03more social responsibility than
  • 01:22:04anybody else stored that population?
  • 01:22:08You're benefiting from it, right?
  • 01:22:10And you're you're getting something,
  • 01:22:13something significant, probably,
  • 01:22:14particularly if your intervention.
  • 01:22:17If they are helping to prove that
  • 01:22:19your intervention is effective,
  • 01:22:21you're going to make some money off of that,
  • 01:22:24and so they had they stand to
  • 01:22:27benefit from their contribution to
  • 01:22:29the development of that knowledge.
  • 01:22:33There we go.
  • 01:22:37This will be our final question.
  • 01:22:38Is there an ethical framework you
  • 01:22:40would invoke around the recent pfizers
  • 01:22:42application for vaccine use in age group
  • 01:22:44in which the data is not yet available?
  • 01:22:50Yeah, that's a great closing question.
  • 01:22:57I think that you know,
  • 01:22:59sort of the emergency use
  • 01:23:03authorization questions. Wait?
  • 01:23:05They raised a whole host of
  • 01:23:08of different issues because.
  • 01:23:10If we make something available
  • 01:23:13before it's been sufficiently tested,
  • 01:23:15that can corrupt the results of our studies.
  • 01:23:21You know, so it's it's.
  • 01:23:25Is it possible to pollute,
  • 01:23:26pollute the data and then there
  • 01:23:29are so many questions you know
  • 01:23:31that come up with regard to?
  • 01:23:33What is fair and appropriate?
  • 01:23:36Should we be be allowing access to something
  • 01:23:38that is being tested on individuals
  • 01:23:40where we have a placebo involved?
  • 01:23:43Or you know there are certain
  • 01:23:45risks involved in the research and
  • 01:23:48then we're allowing individuals
  • 01:23:50outside of the research enterprise
  • 01:23:53to bypass that that process.
  • 01:23:56It's it's really,
  • 01:23:58I think this this should be a seminar
  • 01:24:01inning of itself because there.
  • 01:24:03There's so many issues that emerge,
  • 01:24:06UM, there are a lot of scenarios
  • 01:24:09when historically,
  • 01:24:10particularly with HIV drugs,
  • 01:24:12we saw expanded access to treatment
  • 01:24:16being allowed for people whose lives
  • 01:24:19were on the line and there was a
  • 01:24:22strong argument being made for this.
  • 01:24:24But then.
  • 01:24:26Subsequently those who were involved in the.
  • 01:24:33Activism in obtaining access to drugs
  • 01:24:36outside of trials realized that there
  • 01:24:39was a certain benefit to the drug companies,
  • 01:24:43and.
  • 01:24:44Providing expedited access and.
  • 01:24:50Stale of a product that had not been
  • 01:24:53sufficiently proven to be safe and effective,
  • 01:24:56and ultimately was not having the
  • 01:24:59clinical outcomes that were promised.
  • 01:25:02I think with regard to the backs,
  • 01:25:04the COVID vaccine is a different story.
  • 01:25:06Because, you know,
  • 01:25:08we have seen.
  • 01:25:10Widely established safety and
  • 01:25:12efficacy for older populations,
  • 01:25:14so you know it's it's not a question
  • 01:25:18of whether this is likely to be.
  • 01:25:21Useful to other age groups.
  • 01:25:26But it also just it.
  • 01:25:28It's it's challenging to to
  • 01:25:31bypass the scientific process.
  • 01:25:34You know it's.
  • 01:25:37This is this is a question that I'm
  • 01:25:39not sure I have a complete opinion on,
  • 01:25:42but I think that it deserves a lot
  • 01:25:44of attention and at least I can
  • 01:25:46describe what needs to be considered
  • 01:25:49from an ethical perspective,
  • 01:25:51which you know are the questions
  • 01:25:53of fairness to the participants
  • 01:25:55in the trial and ensuring that we
  • 01:25:59are adequately developing a fully.
  • 01:26:04Useful scientific assessment of of
  • 01:26:06the vaccine in this population.
  • 01:26:09Because we've seen you know,
  • 01:26:11again over and over.
  • 01:26:13Historically scenarios where products
  • 01:26:15have come into the market too soon
  • 01:26:17and they're not fully vetted,
  • 01:26:19and so you know, it's.
  • 01:26:24It's it's. It's important that we
  • 01:26:27whatever expanded access there is that
  • 01:26:30it doesn't interfere with getting a
  • 01:26:32full and accurate assessment of safety
  • 01:26:34and efficacy because without that then
  • 01:26:37we're getting into an experimental
  • 01:26:38realm for the entire population,
  • 01:26:40which is arguably less out of
  • 01:26:43the ethical than having it.
  • 01:26:45Your experimental group in which you're
  • 01:26:47testing something out before it's before,
  • 01:26:49it's broadly distributed.
  • 01:26:52Thank you, thank you.
  • 01:26:53Well, I promise the heart stop at 6:30.
  • 01:26:56Doctor Laura Bothwell thank you so much.
  • 01:26:58This is really been quite informative.
  • 01:27:00There are and and and there are some terrific
  • 01:27:03questions and comments that follow on.
  • 01:27:05People are very much engaged in this
  • 01:27:07and I and I do appreciate everybody who
  • 01:27:09was on the call and who was submitted.
  • 01:27:11These terrific questions and the marvelous
  • 01:27:13information you've shared with us, Laura.
  • 01:27:15This has been a terrific evening.
  • 01:27:17Thank you so much.
  • 01:27:18Such a pleasure. Thanks to
  • 01:27:20everyone who participated.
  • 01:27:23Thank you all very much.
  • 01:27:24We'll see you again in a couple of weeks.
  • 01:27:26I have a goodnight thank you Doctor Bothwell.